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Posts Tagged ‘study’

The drug, Keytruda (pembrolizumab), was tested on more than 600 patients who had melanoma that had spread throughout their bodies. Because so many of the patients in the early testing showed significant long-lasting responses, the study was continued and the FDA granted the drug “breakthrough therapy” status, allowing it to be fast-tracked for approval.

The largest Phase 1 study in the history of oncology, the research was conducted at UCLA and 11 other sites in the U.S., Europe and Australia.

Keytruda, formerly known as MK-3475, is an antibody that targets a protein called PD-1 that is expressed by immune cells. The protein puts the immune system’s brakes on, keeping its T cells from recognizing and attacking cancer cells, said Dr. Antoni Ribas, the study’s principal investigator and a professor of medicine in the division of hematology-oncology at the David Geffen School of Medicine at UCLA.

For many years, when using immunotherapy to fight cancer, doctors’ strategy has been to bolster the immune system so it could kill the cancer cells. But the approach had limited success because PD-1 prevented the immune system from becoming active enough to attack the cancer.

Keytruda, in effect, cuts the brake lines, freeing up the immune system to attack the cancer.

“This drug is a game changer, a very significant advance in the treatment of melanoma,” said Ribas, who also is a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “For patients who have not responded to prior therapies, this drug now provides a very real chance to shrink their tumors and the hope of a lasting response to treatment.”

Judith Gasson, senior associate dean for research at the David Geffen School of Medicine at UCLA and director of the Jonsson Cancer Center, said researchers have long hoped to develop an effective and lasting immunotherapy to fight cancer.

“We have long believed that harnessing the power of our own immune systems would dramatically alter cancer treatment,” she said. “Based upon work conducted over the past two decades, we are beginning to see the clinical benefits of this research in some of the most challenging cancers.”

Generally, about 1 in 10 patients responded to previous immunotherapy drugs. Some of those who responded, however, exhibited long-lived benefits, which sustained scientists’ interest in the method as an effective mechanism to fight cancer.

The response and duration rates for Keytruda were much greater than for previous drugs, Ribas said. In the new study, 72 percent of patients responded to the drug, meaning that their tumors shrank to some degree. Overall, 34 percent of patients showed an objective response, meaning that their tumors shrank by more than 30 percent, and did not re-grow.

Ribas said Keytruda has the potential to be used to treat other cancers that the immune system can recognize, including cancers of the lung, bladder, head and neck.

Survivors’ stories Kathy Thomas, 59, of Torrance, California, was diagnosed in September 2011 with melanoma that had spread to her liver and was invading her left breast. She underwent several therapies that did not work, and she was weakening fast.

“I lost weight. I threw up nearly every day,” Thomas said. “My hair was thinning. I just had no strength at all. I was so sick I had to use a wheelchair.”

Thomas met with Ribas in 2012 but was skeptical about enrolling in a trial to test an experimental therapy. She soon overcame her hesitation.

Since enrolling in the study, Thomas’ tumors have shrunk. She regained her strength and her appetite. She’s out of her wheelchair and walking normally again. She said she has experienced no side effects from the therapy, and she travels monthly to San Francisco to visit her grandson.

Tom Stutz, 74, of Sherman Oaks, California, was diagnosed in June 2011 with melanoma that had spread to his lung, liver and other parts of his body. He didn’t see how he could survive, but he decided to enroll in the clinical trial of Keytruda anyway.

“I wasn’t eating. I was on oxygen. I couldn’t walk,” he said. “When I went into the hospital at the end of May [2012], I didn’t think I was coming out.”

Gradually, though, Stutz started feeling better. Today, he’s no longer on oxygen and walks several miles every day.

“It’s the little things that make me happy now,” Stutz said. “I’m very appreciative that I get to get up in the morning, go into my backyard and see my garden. I’m able to be with my children and grandchildren, go on vacations with them. I was close to the end of the road, as far as you can get to the edge of the cliff, and I was pulled back by this treatment.”

Melanoma incidence rates have been increasing for at least 30 years. An estimated 76,100 new cases of melanoma will be diagnosed in the U.S. in 2014, and nearly 10,000 Americans will die from the disease this year. While melanoma accounts for less than 2 percent of all skin cancer cases, it is responsible for the vast majority of skin cancer deaths, according to the American Cancer Society.

The impact of soy consumption on breast cancer prevention and treatment is not clear although many women believe soy supplementation is beneficial based primarily on results from epidemiological studies. Moshe Shike, M.D., from the Department of Medicine at Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College in New York, NY, and colleagues conducted a randomized placebo-controlled study of the effects of soy supplementation on gene expression and markers of breast cancer risk among women diagnosed with invasive breast cancer. The study, run between 2003 and 2007 at Memorial Sloan-Kettering, enrolled a total of 140 patients who were randomized to either soy supplementation (soy protein) or placebo (milk protein), which lasted from the initial surgical consultation to the day before surgery (range=7-30 days). Tumor tissues from the diagnostic biopsy (pre-treatment) and at the time of resection (post-treatment) were then analyzed. They observed changes in several genes that promote cell cycle progression and cell proliferation among women in the soy group.

The authors conclude, “These data raise concern that soy may exert a stimulating effect on breast cancer in a subset of women.”

In an accompanying editorial, V. Craig Jordan, O.B.E., D.Sc., Ph.D., FMedSci, from the Department of Oncology at the Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, discusses how timing of soy supplementation is critical and reviews the evidence in the literature on phytoestrogens, which are contained in soy, and their known action in breast cancer. He writes, the study by Shike et al. “…illustrates the dangers of phytoestrogen consumption too soon, around menopause, but the biology of estrogen in estrogen-deprived conditions suggests that phytoestrogen could have benefit a decade after menopause.” He cautions that appropriate doses of soy and timing of consumption are critical considerations.

The specific forms of AML and MDS in the current study involve deletions on the arm of a specific chromosome in blood cells (del(5q). In patients with less aggressive forms of del(5q) MDS, the percentage of bone marrow blasts in their blood (the earliest, most immature cells of the myeloid cell line) is less than 5 percent. This means treatment prognosis for those patients typically is good, according to the study’s lead investigator, Daniel Starczynowski PhD, a researcher in the division of Experimental Hematology and Cancer Biology, part of the CBDI at Cincinnati Children’s.

“Unfortunately, a large portion of del(5q) AML and MDS patients have increased number of bone marrow blasts and additional chromosomal mutations,” Starczynowski said. “These patients have very poor prognosis because the disease is very resistant to available treatments such as chemotherapy and radiation. Finding new therapies is important and this study identifies new therapeutic possibilities.”

The researchers conducted their study in human AML/MDS cells and mouse models of del(5q) AML/MDS. They found that reduced expression of a certain gene in blood cells (miR-146a) led to activation of a molecular signaling network involving several components of NF-kB, one of which involved a protein called p62 — a critical regulator of cell metabolism, cellular remodeling and certain cancers.

Deletion of the miR-146a gene led to overexpression of p62, which caused sustained activation of what researchers identified as an NF-kB signaling network. This fueled the survival and aggressive growth of leukemic cells in cells and in mouse models.

Earlier attempts in previous studies to directly inhibit NF-kB (a key molecular facilitator to the leukemic process) have not proven successful, according to investigators on the current paper. So the authors performed follow-up laboratory tests to look for possible vulnerabilities to NF-kB and a potential workaround by targeting instead p62 within the NF-kB signaling network.

The researcher next tested inhibiting/knocking down p62 as an experimental treatment strategy in mouse models of leukemia and in human cells. The authors reported that targeting p62 prevented expansion of leukemic cells in mouse models and reduced the number of leukemia cell colonies by 80 percent in human AML/MDS cells.

Starczynowski stressed that significant additional research is needed to further verify the findings and learn more about the molecular processes involved. He also cautioned that laboratory results in mouse models do not necessarily translate to humans, and it isn’t known at this time how the findings might be directly applicable to clinical treatment.